Cause Of Chronic Mucocutaneous Candidiasis Research Articles

STAT1 Mutations in Chronic Mucocutaneous Candidiasis Diagnosed in an Adult.

A 30-year-old man presented with oral candidiasis and a history of lung abscess. He experienced recurring oral and skin candidiasis in childhood but spent long periods without any infections. Therefore, immunodeficiency was suspected. T and B lymphocyte and natural killer cell counts as well as immunoglobulin levels were normal. Human immunodeficiency virus test results were negative. Therefore, we suspected chronic mucocutaneous candidiasis (CMC). The signal transducer and activator of transcription (STAT) mutation, the leading cause of CMC, was detected by exome sequencing. Most cases of STAT1 mutations are diagnosed in childhood, but a few are diagnosed in adulthood because Candida infections may not be severe.

Human STAT1 gain of function with chronic mucocutaneous candidiasis: A comprehensive review for strengthening the connection between bedside observations and laboratory research.

Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF. The effectiveness of JAK inhibitors as a therapeutic option has been established, although further investigation of their long-term utility and side effects is needed. In contrast to the advancements in treatment options, the precise molecular mechanism underlying STAT1 GOF remains undetermined. Two primary hypotheses for this mechanism involve impaired STAT1 dephosphorylation and increased STAT1 protein levels, both of which are still controversial. A precise understanding of the molecular mechanism is essential for not only advancing diagnostics but also developing therapeutic interventions. Here, we provide a comprehensive review of STAT1 GOF with the aim of establishing a stronger connection between bedside observations and laboratory research.

A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections.

Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies. After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry. We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls. Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests.

The pathogenic T387A missense mutation in the gene encoding signal transducer and activator of transcription 1 exhibits a differential gene expression profile

Heterozygous gain-of-function (GOF) mutations in the interferon-driven transcription factor STAT1 (signal transducer and activator of transcription 1) cause chronic mucocutaneous candidiasis (CMC). In this study, we characterized the molecular basis of a CMC-associated missense mutation by introducing a threonine-to-alanine exchange in the STAT1 DNA-binding domain at position 387. This substitution had previously been described in a CMC patient with suppurative eyelid infection and cutaneous abscesses, which are both unusual symptoms in this immunodeficiency. The STAT1-T387A mutant generated was compared to the wild-type protein and, in addition, to the missense mutant in the neighbouring position 386. Our results showed that the T387A mutant displayed distinct properties different from the wild-type molecule, namely elevated levels of tyrosine phosphorylation in conjunction with increased DNA-binding activity, hyperactive transcriptional regulation, and prolonged nuclear accumulation. The elevated tyrosine phosphorylation of the T387A mutant did not result in an increased mRNA production above the level of the wild-type molecule for all transcripts tested, indicating that the transcriptional activity of this mutant is largely gene-dependent. Nonetheless, these data demonstrate that the pathogenic T387A mutation associated with an atypical CMC symptomatology is biochemically similar to other well-characterized GOF mutants, while the H386A mutant was indistinguishable from the wild-type molecule. Our findings are in line with the assumption that the phenotype of this dominant STAT1 GOF mutation probably results from a disturbed shift in the equilibrium between the parallel and antiparallel dimer conformation, which is required for physiological gene activation.

Dysregulatory syndromes: the role of signal transducers and activators of transcription.

A comparative description of dysregulatory syndromes with mutations in signal transducer and activator of transcription (STAT) genes. STAT 1, 3 and 5b loss of function (LOF) and gain of function (GOF) mutations are a heterogeneous group of genetic disorders that range from immunodeficiency (ID) to autoimmune disease (AID), depending on the underlying signalling pathway defect. Between them, there are clear overlapping and differences in clinical presentation and laboratory findings. Dysregulatory syndromes due to LOF and GOF mutations in STAT1, 3 and 5b are a particular group of primary immunodeficiencies (PIDs) in which AID may be the predominant finding in addition to infections susceptibility. STAT1 GOF mutations were described as the major cause of chronic mucocutaneous candidiasis, while activating STAT3 mutations result in early-onset multiorgan autoimmunity and ID. Human STAT5b deficiency is a rare disease that also involves ID and severe growth failure. In recent years, the identification of the genes involved in these disorders allowed to differentiate these overlapping syndromes in order to choose the most effective therapeutic options.

HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis

Signal transducer and activator of transcription 1 (STAT-1) gain-of-function (GOF) mutations cause chronic mucocutaneous candidiasis (CMC), a disease associated with Candida albicans and Staphylococcus aureus infection. Patients suffer from dysegulated immune responses due to aberrant cell programming and function. We investigated the effect of inhibitory molecules targeting histone deacetylases (HDACi) on the immune responses of peripheral blood mononuclear cells (PBMCs) of healthy controls and patients with CMC towards microbes relevant for CMC. PBMCs cells were pretreated with HDACi and challenged with C. albicans or S. aureus. Innate and adaptive cytokines were measured in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). We assessed the effect of HDAC inhibitors on T helper type 1 (Th1) and Th17 cells and measured STAT-1 and STAT-3 phosphorylation using flow cytometry. Panobinostat, a pan-HDAC inhibitor, strongly inhibits innate and adaptive cytokines upon challenge with C. albicans or S. aureus. Specific inhibitors (entinostat or RGFP966) also had a tendency to lower production of most innate cytokines in CMC patient cells. Entinostat and RGFP966 increased the production of interleukin (IL)-22 specifically after S. aureus challenge in patient cells. In healthy and control cells, entinostat and RGFP966 treatment down-regulated STAT-1 phosphorylation while pSTAT-3 levels remained stable. HDACi modulate cytokine production in response to C. albicans and S. aureus. Pan-inhibitors lower overall cytokine production, whereas specific inhibitors confer a selective effect. Entinostat and RGFP966 are promising therapeutic candidates to treat STAT-1 GOF due to their capacity to restore IL-22 production and decrease STAT-1 phosphorylation; however, their inhibition of innate cytokines poses a possible risk to secondary infections.

Chronic Mucocutaneous Candidiasis Due to Gain-of-Function Mutation in STAT1

Background: Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of primary immunodeficiency diseases characterized by susceptibility to chronic or recurrent superficial Candida infection of skin, nails, and mucous membranes. Gain-of-function mutations in the STAT1 gene (STAT1-GOF) are the most common reported cause of CMC. We describe here the clinical and genetic findings for 3 patients with CMC caused by novel gain-of-function mutations in STAT1-GOF.

Mutation in the C receptor of Interleukin 17, as a cause of Chronic Mucocutaneous Candidiasis

Background: The humoral and cellular immunity plays a preponderant role in the etiopathogenesis of esophagitis, for which the majority of the patients who present this pathology will have some type of immune system. Methods & Materials: Patient of 36 years of age, family history of Hiper IgE syndrome, consulted for abdominal pain, enterorrhagia, weight loss, dysphagia and vomiting. The physical examination shows important muguet. Regarding to personal history, it is recognized that thepatients episodes of candidiasis esophagitis from the age of 6 years and cutaneous plasmocytoma located in the wing of the nose that required surgical extirpation. Results: In endoscopic exploration, the esophagus appears hyperemic, with yellowish mucous plaques that adhere firmly, with rough and friable underlying surface after removal. Pathological anatomy informs esophagitis, with presence of yeasts compatible with Candida on the mucosal surface. In the stomach, the lamina propria presents edema with lymphocyte hypercellularity. Microbiology: Candida albicans. The patients begins treatment with Fluconazole. Laboratory: HIV negative Elisa, non-reactive HBsAg, non-reactive HCV antibodies. IgG 1727 mg/dl, IgA 271 mg/dl, IgM 154 mg/dl, IgE 172 mg/dl. CD3 2123 (76.8%), CD4 1024 (46.6%), CD8 674 (24.4%), CD19 498 (15.8%). A molecular biology study was carried out in search of mutations in the AIRE gene, sequencing of exons and adjacent intronic sequences, showing no alterations compatible with mutation. The mutation of this gene is linked to several autoimmune diseases, such as hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidiasis. In a new molecular study, it shows mutation in the C IL 17 receptor (IL17RC). This interleukin is related in the antifungal defense. Conclusion: Interleukin 17 participates in the development of autoimmunity, inflammation and tumor immunity, playing an important role in the defense against bacterial and fungal infections. The blocking of IL-17 signaling due to the mutation of its receptor prevents the formation of germinal centers and reduces the humoral response. The discovery of this mutation is a rarity, and plays an important role in defense against infectious diseases. In this clinical case, this mutation predisposes to the recurrence of chronic mucocutaneous candidiasis.

Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome.

STAT1 mutations cause chronic mucocutaneous candidiasis (CMC), while STAT3 mutations cause hyper-IgE syndrome (HIES). CMC and HIES patients have T helper (Th) 17 defects suffering from mucosal Candida infections, but only patients with HIES show an allergic phenotype with eczema, eosinophilia and high IgE levels. We investigated whether differential Th2 and Th9 responses may explain the clinical differences. Peripheral blood mononuclear cells of patients with CMC (n = 4), patients with HIES (n = 4), patients with atopic dermatitis (n = 4) and healthy volunteers (n = 13) were stimulated with Candida and Staphylococcus aureus, with and without IL-4. The cytokines IL-5, IL-13, IL-9, IL-17 and TGFβ and regulatory T cells were measured in cell culture supernatants by ELISA or flow cytometry, respectively. Peripheral blood mononuclear cells of patients with CMC showed a significantly impaired production of the Th2 cytokines IL-5 and IL-13, especially in the presence of IL-4. Moreover, IL-9 production was significantly lower in patients with CMC compared to healthy controls. In contrast, patients with HIES and patients with AD showed normal IL-5 and IL-13 production, while IL-9 production was significantly lower in patients with HIES compared to healthy controls. Although TGFβ was involved in the IL-4-induced IL-9 production, TGFβ levels and the frequency of regulatory T cells did not differ between patients with HIES and controls. Flow cytometry analysis demonstrated an IL-9+ IL-17+ CD4+ subset in healthy controls after stimulation with Candida which was less present in patients with HIES. Patients with CMC have a general Th defect including Th2 and Th9, while patients with HIES have normal Th2 cytokines. These differences are in line with their clinical presentation. Surprisingly, the allergic cytokine IL-9 was deficient in both HIES and CMC, suggesting a Th-17-derived origin.

A Young Adult Male with Chronic Mucocutaneous Candidiasis (CMC) with Signal Transduction and Activator of Transcription 1 (STAT 1) Mutation and Progressive Multifocal Leukoencephalopathy (PML)

M O N D A Y 600 Variable Presentations of Gain of Function STAT1 Mutations within a Single Institution with Features Beyond Chronic Mucocutaneous Candidiasis Sheila M. Bina, MD, Jenni Y. Yoon, MD, Jennifer W. Leiding, MD; University of South Florida, St. Petersburg, FL. RATIONALE: Gain of function (GOF)mutations in signal transducer and activator of transcription 1 (STAT1) are a major cause of chronic mucocutaneous candidiasis (CMC). Susceptibility to viral, bacterial, fungal, and mycobacterial infections can also occur. In addition to infection susceptibility, patients with GOF-STAT1 mutations suffer from many other manifestations. METHODS: Retrospective chart reviews were performed on 5 patients with GOF-STAT1 mutations to identify specific infectious susceptibility and other immunologic manifestations. RESULTS: All 5 patients identified have mutations in the coiled-coiled or DNA binding domains of STAT1, all consistent with gain of function. Four patients have CMC, 1 has recurrent herpes simplex virus stomatitis, 1 had Mycobacterium fortuitummediastinal lymphadenitits, and 2 have recurrent sinopulmonary infections. One patient presented at 5 months of age with immunodysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) like manifestations including severe refractory diarrhea, diabetes, and failure to thrive. Successful matched unrelated bone marrow transplant was performed at 3 years of age. In addition to CMC, one patient had a giant hand granuloma caused by Trichopyton tonsurans. Other non-infectious manifestations include generalized seizures, autoimmune hemolytic anemia, recurrent thrombosis, and squamous cell carcinoma. CONCLUSIONS: In addition to CMC, these patients demonstrate broad infectious susceptibility and many other manifestations of GOF-STAT1 mutations including IPEX-like disease, vascular disease, autoimmunity, and malignancy.

Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding

Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): Chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding

Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival

Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival